Remifentanil is an ultra-short acting mu-opioid receptor agonist that allows for shorter mechanical ventilation in Intensive Care Units and may also reduce duration of surgery and anesthesia.1,2

It is useful for spinal procedures, where rapid recovery, immediate neurological examination and hemodynamic stability, as well as a minimal effect on electrical evoked potential monitoring are desirable.3-5

A study of anesthetic techniques during spinal fusion surgery revealed earlier spontaneous ventilation and earlier movement of the hands and feet when remifentanil was used in comparison to alfentanil-propofol.6

Our Medical Center serves as a tertiary spine center that attracts the majority of pediatric spine disorders in Israel, pediatric idiopathic scoliosis (IS) being the most common entity.

In 2003, the anesthesiologists at our medical center started using remifentanil.

In 2005, we replaced morphine with remifentanil infusion during anesthesia for scoliosis surgery.

Our aim was to evaluate the efficacy of remifentanil-based anesthesia by comparing remifentanil and morphine-based groups.

This study retrospectively reviewed the records of children with pediatric scoliosis who underwent primary spinal fusion, by instrumentation of the thoracic-lumbar spine, at our Medical Center between the years of 1998 and 2007. During this period, the surgeons and chief anesthesiologists who performed the procedures remained unchanged. The study was approved by the hospital's Ethics Committee.

The study included patients with scoliosis of idiopathic etiology only (excluding children of other etiological groups, such as neuromuscular, neurofibromatosis, congenital scoliosis, etc., due to a small number of observations). A scoliosis curve of >50° in adolescent patients was the main indication for surgery.

Echocardiography, chest X-ray and spirometry were performed for all the participants before the surgical procedure was carried out.

A combination of screws, hooks and two titanium rods was used in all patients.

The children who were included were divided into two groups according to the anesthetic regimen administered. In both groups, large-bore intravenous access with a fluid warmer and an intra-arterial line for monitoring was routinely applied. Routine pre-medication included oral midazolam 0.15-0.2 mg/kg (mean dose 8 mg) and intramuscular or intravenous morphine (0.1-0.15 mg/kg) in combination with oral atropine (0.5 mg). For muscle relaxation, IV pancuronium bromide 0.05-0.1 mg/kg was administered, while succinylcholine (1 mg/kg) was administered in cases of suspected difficult intubation. In both groups, anesthesia was induced with a dose of 2 to 2.5 mg/kg propofol. For the maintenance of anesthesia, inhaled isoflurane was used. The minimal alveolar concentration of isoflurane was maintained at a level of 0.5 to 1.5.

Controlled hypotension was induced in order to limit intraoperative blood loss. Since all the patients in the current study were teenagers, adult blood pressure limits with a reduction of systolic blood pressure to 80-90 mm Hg and a reduction of mean arterial pressure to 50-60 mm Hg were used. The use of vasodilator agents such as nitroglycerin 0.5-2 mcg/kg/min or nitroprussid 0.5-2 mcg/kg/min was added as needed during surgery.

Somatosensory and motor evoked potentials were routinely recorded, combined with Stagnara's wake-up test whenever indicated.

Routine complete blood count (CBC), electrolytes and clotting studies were performed during surgery.

Normal saline, Cell Saver® autologous blood recovery (Haemonetics Corp., Braintree, MA, USA), packed red blood cells (PRBC), fresh frozen plasma (FFP), platelets and cryoplasma units were given according to estimated blood loss, intraoperative blood test results and hemodynamic status.

In the first group, analgesia was induced by an IV morphine bolus (1-1.5 mg/kg), and fentanyl (2 to 3 mcg/kg) was administered according to hemodynamic responses (a change in heart rate or blood pressure ≥20% from baseline) during surgery (operations performed before mid 2005).

In the second group, analgesia was induced by an infusion of IV remifentanil (from mid 2005 and thereafter). Remifentanil infusion was begun at a rate of 0.2 mcg/kg/min and subsequently titrated in increments of 0.05 mcg/kg/min according to hemodynamic responses (a change in heart rate or blood pressure ≥20% from baseline). IV morphine (0.1-0.3 mg/kg) was administered 30 minutes before the end of surgery for analgesia control.

At the end of surgery, an attempt at extubation was performed in the recovery room. Extubation criteria were: patient awake, calm and cooperative; hemodynamic stability; negative inspiratory force >20 cm H₂O; respiratory rate <30/min, PaCo₂ <50 mm Hg; and PaO₂ >70 mm Hg with FiO₂ <0.4. Patients who were extubated and stable for at least 2 hours were transferred to the Pediatric Orthopedic Ward. Those who did not meet the extubation criteria or who, according to the anesthesiologist's judgment, needed stricter follow-up were transferred to the Pediatric Intensive Care Unit (PICU). Antibiotics were routinely administered before beginning the surgery, and appropriate antibiotic coverage was used until drain removal. Whenever fever of a suspected infectious etiology appeared, antibiotic cover was adapted according to culture results or current guidelines. Follow-up included daily physical examinations (including attentive neurological assessment), vital signs monitoring, routine blood tests, chest X-rays and other ancillary tests as required. The same extubation criteria were implemented in the PICU. Patients who remained stable for at least 24 hours after extubation and had no active bleeding from the operation site or drains were transferred to the Pediatric Orthopedic Ward. The attending physicians recorded any complications and events during the early postoperative period, which was defined as the hospitalization period until discharge to orthopedic rehabilitation.

Postoperative pain control was administered in both groups using a combination of morphine (0.1 mg/kg/dose) every 4 hours and ibuprofen [a non-steroidal anti-inflammatory agent (NSAID)], (10 mg/kg/dose) every 6 hours. A numerical pain scale with a range of 0 to 10 was used to gauge a patient's pain, where zero indicated no pain and 10 indicated the worst pain. Mild to moderate pain (2-6 on the scale) was treated with NSAIDs and severe pain was treated with narcotics.

Demographic data and a list of surgery-related details were collected and compared between the groups (see below). Early postoperative complications, the rate of postoperative blood product administration and the length of hospitalization in the Pediatric Intensive Care Unit were also recorded and compared.

The classification of major and minor complications was based on previous studies published on the subject (Table 1).7

Remifentanil was found to be an effective anesthetic agent for pediatric scoliosis repair surgery. The use of remifentanil enabled better achievement of hypotension during surgery and shorter operating times, and made reaching earlier spontaneous ventilation possible with less of a need for ICU hospitalization and no increase in significant complications.

Our database included 36 children in the remifentanil group vs. 84 children in the morphine group, all of whom were diagnosed with idiopathic scoliosis.

Comparison of demographic parameters between the groups yielded no significant differences, which is an indication of database homogeneity. Comparison of surgery-related parameters between the groups yielded three significant results: shorter surgery length, sparing of vasodilator agents for achievement of hypotension during surgery and rapid extubation at the end of surgery.

In this study, we retrospectively reviewed the charts of patients spanning nearly a decade of cases. Though the surgeons and chief anesthesiologists did not change for the period studied, other minor technical aspects of clinical care developed over the years, and these factors could have contributed to the outcomes. As the current study deals with about a decade of surgical experience, a learning curve for the surgeons could have attributed to the shorter length of surgery. The longer waiting time that was required for the wake-up test in the morphine group may have slightly contributed to the longer surgery time in this group. Although it is difficult to confirm a clear link between the length of the operation and the type of opioid used by the anesthesiologist as a single factor, we do think that this study shows easier achievement of hypotension, which probably contributed to shortening the length of the operation. This fact was reported in previous studies2 for different orthopedic procedures in adults where the use of remifentanil allowed a reduction in time of surgery and anesthesia. The controlled hypotension induced by remifentanil is possibly related to the marked reduction in systemic vascular resistance that is not related to histamine release.9 Vasodilatation is mainly an endothelium-dependent phenomenon, involving prostacyclin and nitric oxide release from the endothelium.10 Remifentanil also suppresses the sympathetic nervous system11,12 and inhibits calcium channels in human mesenteric arteriolar smooth muscle cells.13

In the current study, no significant difference in blood loss between the groups was noted, despite the shorter operating time in the remifentanil group.

Sedative drugs are usually used as premedication in children in order to minimize psychological trauma related to anesthesia and surgery.14 In the current study, all the 120 participants received a similar basic premedication protocol before the induction of aesthesia; therefore, we believe that the premedication treatment in this type of surgery, which lasted from 4 to 5 hours, had minimal influence on early postoperative period complications.

Pulmonary complications (PPC) were the most often occurring complications recorded in the current study, with no significant difference between the groups. PPCs are one of the risks related to surgery and anesthesia and might exacerbate postoperative morbidity, mortality and longer hospitalization. A recent review15 published on this topic revealed a wide range of PPC incidences (2-40%). Age, co-morbidity, the use of general anesthesia and the overall surgical insult were the highest risk factors for PPC. Since all the participants in the current study were young, healthy adolescents and had similar spirometry findings and no cardiac pathologies, we believe that PPC was more likely to be associated with surgical insult.

Six patients in the remifentanil group, in comparison to 2 patients in the morphine group, were directly hospitalized in the Pediatric Orthopedic Department following surgery. They all had a benign postoperative course (p<0.0004). This difference indicated a better immediate term condition for the remifentanil children who were rapidly extubated, respiratorily and hemodynamically stable, and transferred immediately to the Pediatric Orthopedic Department. Accordingly, randomized controlled trials demonstrated that remifentanil allows for earlier extubation after prolonged surgery, even when compared with other short acting opioids such as sufentanil.16 Furthermore, while no child in the remifentanil group required postoperative mechanical ventilation, all those in the morphine group did. Three of them were extubated at more than 24 hours following surgery (which again highlights the problem of extubation following morphine utilization).

Our database did not show a reduced length of PICU hospitalization with the use of remifentanil, although such results (including reduction of mechanical ventilation time) have been reported in the adult population.1,2

Had we included the 8 patients who were immediately transferred post surgery to the Pediatric Orthopedic Department in the hospitalization length analysis, our results would probably have been similar to the findings in other studies.

One of the limitations of our study was the large group of children administered a mixture of morphine and fentanyl, which are both relatively long acting opioid agents but have differing pharmacokinetics. In comparison to morphine, fentanyl is 50-100 times more potent, has a more rapid onset of action and has a lesser half-time.17 Fentanyl was chosen by the anesthesiologist as an additive opioid to morphine, as needed during the surgical procedure in the first group, because of its properties. The therapeutic potency of remifentanil is somewhat less than that of fentanyl,18 and a comparison of the total opioid use per hour revealed that the remifentanil group required a relatively higher dose. Achieving controlled hypotension during surgery is probably the main reason for requiring a higher dose of opioids in the remifentanil group.

Cessation of remifentanil at the end of the surgical procedure may lead to hyperalgesia. Several studies have described the possibility of developing acute opioid tolerance during infusion of remifentanil in pediatric scoliosis surgery, when compared with intermittent morphine boluses.19,20 These studies reported significantly increased postoperative morphine consumption in the remifentanil group when a patient-controlled analgesia (PCA) device was used. Contrarily, our study showed no difference in analgesia use between the groups in the postoperative period. We believe that this finding can be partially explained by the fact that a PCA device was not used in our Pediatric Orthopedic Department at the time of the study and also by the concomitant use of NSAIDs postoperatively, especially when mild to moderate pain was revealed according to the pain scale used. Another factor possibly contributing to the reduction in hyperalgesia was the administration of morphine as premedication and at 30 minutes before the end of surgery in the remifentanil group. A combination of opioid agonists or opioid rotation has demonstrated some success in decreasing or preventing opioid-induced hyperalgesia according to some studies.21 Theoretically, the use of a pure opioid agonist with different receptor binding characteristics and a longer duration of action than remifentanil may be beneficial when trying to prevent opioid-induced hyperalgesia.

The financial cost difference between anesthesia using remifentanil compared to morphine is also an important issue. In our hospital, the average cost of remifentanil for one operation is 200$ vs. 5$ for morphine. However, by using remifentanil, the overall time of surgery is shortened, and other vasodilator drugs, which are necessary for inducing hypotension when administering morphine anesthesia, can be spared. Furthermore, several studies have illustrated that remifentanil usage during anesthesia may allow for smaller doses of other short-acting anesthetic agents.22,23 In addition, more patients with remifentanil anesthesia skipped PICU hospitalization in the current study. Other previous studies have also proven a reduction in PICU admission after other major surgical procedures due to remifentanil use.24 In summation of the above, we could conclude that the cost difference might be inconsequential.

Our study is important since, for the first time, we demonstrate the immediate efficacy and possible cost effectiveness of remifentanil use in pediatric scoliosis spine surgery. Follow-up demonstrated no difference between our two groups. However, the period of follow-up in the remifentanil group was relatively short term and we still need to wait and see if long term consequences arise.

The unique properties of remifentanil (organ-independent metabolism, lack of accumulation, rapid offset of action) and the favorable performance thereof (minimal effect on electrical evoked potential monitoring, time and vasodilatatory agent economization, fast and predictable extubation and quicker ICU discharge) render it a convenient opioid.

In conclusion, remifentanil use can shorten operating time and facilitate earlier spontaneous ventilation and extubation, with less of a need for intensive care hospitalization and no increase in significant complications. Whether our findings are relevant to non-idiopathic scoliosis patients has yet to be established in a similar study on neuromuscular and cerebral palsy patients with scoliosis.